George Alangaden MD Professor of Medicine Division of Infectious Diseases Wayne State University Detroit MI [email protected]Review factors that can delay diagnosis of TB Discuss features that suggest “Think TB” Clinical presentations Epidemiological Correlates Utility of newer diagnostic tests for effective triage of patients with suspected TB in HCF 57 yr‐old Malaysian male, resident in USA for 15 yrs Autologous hematopoeitic stem cell transplant for non‐Hodgkin’s lymphoma Relapsed NHL left chest wall, treated with radiation Undergoes allogeneic HSCT for progressive NHL D+17 after HSCT develops fever, no other complaints. Fever responds to empiric cefepime Re‐admitted after 1 week with fever
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Think TB Alangaden finalglobaltb.njms.rutgers.edu/downloads/courses... · 4925 SOTs* –13 TB cases ‐Incidence 264/100,000 OR for kidney transplant 4.59 Median time to onset of
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George Alangaden MDProfessor of Medicine
Division of Infectious DiseasesWayne State University
Review factors that can delay diagnosis of TBDiscuss features that suggest “Think TB”Clinical presentationsEpidemiological Correlates
Utility of newer diagnostic tests for effective triage of patients with suspected TB in HCF
57 yr‐old Malaysian male, resident in USA for 15 yrsAutologous hematopoeitic stem cell transplant for non‐Hodgkin’s lymphomaRelapsed NHL left chest wall, treated with radiationUndergoes allogeneic HSCT for progressive NHLD+17 after HSCT develops fever, no other complaints.Fever responds to empiric cefepimeRe‐admitted after 1 week with fever
Fever resolves with antibiotic therapyRe‐admitted after a month with high fevers and mildSOB
Lung biopsy fibrosis, reactive changes, possible nuclear inclusions, no lymphoma.
Culture of lung tissue at 4 weeks grows M. tuberculosis.
Total time from onset of symptom to diagnosis of TB = 44 days
Absence of coughOther explanations for feverResponse to empiric antibioticsAFB smear negativeNo granulomas on histopathologyUnderlying conditions that could have caused infiltrates in an immunocompromisedpatient e.g. fibrosis, lymphoma, fungal infection, etc
184 culture+ TB patients, NYC, 1994Type of delay No. days
AFB smear+ AFB smear ‐ P value
Total delay 57 35 79 <0.001
HC P delay* 15 6 31 <0.001
Patient delay 25 NA NA NA
Factors associated with HCP delay Adjusted Odds Ratio
158 patients TB culture positive, Maryland, 2000‐01Covariate associated with HCP delay Days of delay
Private physician visit / ED visit / Public Health clinic visit 51 / 18 / 10
CXR done / not done 15 / 69
CXR cavitation / no cavitation 6 / 17
AFB smear + / AFB smear ‐ 18 / 37
AFB culture done / not done 6 / 56
Antibiotics prescribed / not prescribed 39 / 15
Golub JE. Int J Tuberc Lung Dis 2005;9:992-98
183 patients, culture positive TB, London UK20/42 (48%) who got antibiotics had symptom improvement unrelated to drug classMedian time to TB diagnosis >8 weeks in 50% of those who got antibiotics vs zero if no antibiotics
233 patients culture positive for TB, Baltimore, US16/33 treated with fluoroquinolone for suspected CAPMedian time to TB diagnosis 21 days in FQ treated patients vs 5 days in non‐ FQ treated patientsEmergence of resistance to FQ in 11%3
http://www.michigan.gov/mdch (accessed June 7, 2010)
National rate 2008 was 4.4 = (12,904 cases)
185 new cases of TB
http://www.michigan.gov/mdch (accessed June 7, 2010)
Recent close or prolonged contact with TB patientPrior inadequately treated TBChest radiographs with features of prior TBImmunosuppression (prednisone>15mg/d/30d) Conditions associated with risk of reactivation
French registry – 3 year review69 cases of TB in patients receiving inflixamab, adalimumab or etanerceptNone received treatment for LTBI
Agent Incidence ratios for TBInfliximab 18.6Adalimumab 29.3Etanercept 1.8
Tubarch F. Arthritis Rheum 2009;60:1884-94
Wallis RS. Clin Infect Dis 2005;41:S194-8
1NYC (Single Center 1988‐2007)4925 SOTs* – 13 TB cases ‐ Incidence 264/100,000 OR for kidney transplant 4.59Median time to onset of TB after SOT – 11 mo
* Solid organ transplants1 Lopez de Castillo. Transplant Infect Dis 2010;12:106-1122 Torres-Cisneros Clin Infect Dis 2009;48:1657-65
Test Time to result
Sputum specimens x 3, 8‐24 hrs apart for AFB microscopy
1‐3 days
Mycobacterial cultures 2‐4 weeks
Drug‐susceptibility testing for INH, RIF, and EMB
4‐8 weeks
Sputum specimens x 3, 8 hrs apart, one specimen early‐morning sample plusIn house TB lab 24/7
1. Reduction in time to AFB smear status2. Earlier removal of patient from AFB
isolation
AFB smear microscopy of respiratory specimens:Sensitivity of 45%‐80% in culture positive TBPPV 50%‐80% for TB where NTM is common
NAAT in AFB smear positive cases:PPV of >95% in settings where NTM is common
NAAT In AFB smear negative casesSensitivity is 74% and specificity 94%
Can rapidly confirm MTB in 50%‐80% of AFB smear negative and culture positive respiratory specimens
MMWR. 2009;58:7-10. Dinnes j. Health Technology Assessment 2007:11;1-196.Moore DF. Diagn Microbiol Infect Dis 2005;52:247-54
Varghese G.M. et al. Value of differential identification of MTB and NTM using enhanced amplified mycobacterium tuberculosis direct test (EMTD). ICAAC, 2007, Abstract# D-1573
Test Mean turn around time P‐value
E‐MTD 1.5 days <0.001
Culture identification 19.9 days
Result Culture Identification – No. specimens
MTB NTM*
E‐MTD positive 42 0
E‐MTD negative 0 20
* M. avium complex=17, M. chelonae=1, M. xenopi=1, M.kansasii=1
Send first AFB smear positive sputum sample to MDCH TB lab for MTB PCR MDCH report of MTB ± status within 24 hr
1. Significant reduction in time to confirmation of TB
2. Early removal of patient from AFB isolation3. Avoidance of unnecessary empiric TB therapy4. Avoidance of unnecessary contact investigation
Liverpool UK, NAAT test also detected rifampinresistance
MTB confirmed or ruled out in <2 weeks in 86% of NAAT tested suspected pulmonary TB cases vs 7% using cultureClinical impact in 39% of 51 patients tested using NAAT▪ 3 patients unnecessary TB treatment stopped▪ 7 patients treatment continued▪ 4 situations contact investigation averted▪ 2 patients MDR‐TB detected▪ 31 patients at risk for resistance MDR‐TB ruled out
Taegtmeyer M. Thorax 2008;63:317-321
1151 respiratory specimens/638 pulmonary TB suspected patients, MarylandNAAT – amplified MTB Direct test (MDT) of respiratory specimens compared to non‐MTD use period
Test used
Duration of non‐indicated TB treatment
NAAT 6 daysCulture 31 days
Guerra RL. Chest 2007;132:946-51
58 patients with AFB smear‐positive on respiratory sample admitted to AFB isolation
Mean isolation time for 5.4 days since use of E‐MTD vs 19 days using culture identification
Estimated cost savings per patient ‐ $6800
Diagnosis of TB or “Think TB” is a cumulative pathway that includes:Clinical picture Epidemiological factorsRadiographySmear microscopy + NAATCulture
Newer NAATs results in rapid and more effective management of pulmonary TB in healthcare settings